Role of Hepatitis B virus X protein in HBV replication.

肝细胞癌与慢性乙型肝炎感染的关系 病毒(乙肝病毒)引起了人们对了解感染乙肝病毒如何增加风险的极大兴趣 治疗肝癌。基于对感染土拨鼠肝炎病毒的土拨鼠的研究，我们假设 包括人类乙肝病毒在内的所有哺乳动物肝病毒的X蛋白(HBx)对病毒是必不可少的 复制。也有证据表明，HBx有助于肝细胞癌的发展。HBX激活了许多 细胞信号是级联的；然而，这是如何实现的还不清楚。大多数研究都试图 确定HBx在乙肝病毒复制中的重要作用，并了解HBx如何调节细胞 在肝肿瘤来源的肝细胞系中进行了信号转导。使用不朽的或 与真正的肝细胞相比，转化的肝细胞缺乏生物学相关性。我们 已经证明HBx的一个关键活性是调节细胞内钙信号通路。这 该提案旨在利用原代培养的大鼠肝细胞了解HBx的关键活性，并确定 这些活动如何影响肝细胞生理和乙肝病毒复制。目标1中的研究将描述 HBx激活肝细胞钙信号通路的分子机制及其机制 影响乙肝病毒复制。AIM 2的研究将集中在HBx和线粒体之间的相互作用 以及这如何影响肝细胞生理和乙肝病毒复制。目标3特别侧重于监管 HBx单独表达或在复制过程中表达的细胞凋亡。尽管HBX的基本活动是 可能保存在肝细胞中与转化细胞相比，其大小、持续时间和复杂性 这些活性在原代肝细胞中可能有所不同。对原代大鼠肝细胞的研究结果应该 更准确地反映真实感染细胞的状态，澄清不同的HBx活性 已有报道，并提供了对HBx在乙肝复制过程中的作用的更深入的了解。

The association between hepatocellular carcinoma (HCC) and chronic infection with the human hepatitis B virus (HBV) has generated considerable interest in understanding how infection with HBV increases the risk for liver cancer. Based on studies in woodchucks infected with the woodchuck hepatitis virus, it is assumed that the X protein (HBx) of all mammalian hepadnaviruses, including human HBV, is essential for viral replication. There is also evidence that HBx contributes to the development of HCC. HBx activates many cellular signaling cascades; however, how this is accomplished is unclear. Most studies that sought to identify the essential role of HBx during HBV replication, and understand how HBx regulates cellular signaling pathways, were performed in liver cell lines derived from liver tumors. The use of immortalized or transformed hepatocytes suffers from its lack of biological relevance compared to authentic hepatocytes. We have demonstrated that a key activity of HBx is regulation of cellular calcium signaling pathways. This proposal aims to understand key activities of HBx using cultures of primary rat hepatocytes and to determine how these activities influence hepatocyte physiology and HBV replication. Studies in AIM 1 will characterize the molecular mechanism of HBx activation of calcium signaling pathways in hepatocytes and how this influences HBV replication. Studies in AIM 2 will focus on the interaction between HBx and mitochondria and how this impacts hepatocyte physiology and HBV replication. AIM 3 specifically focuses on regulation of apoptosis by HBx expressed alone or during HBV replication. Although the fundamental activities of HBx are likely preserved in hepatocytes as compared to transformed cells, the magnitude, duration and complexity of these activities may differ in primary hepatocytes. Result from studies in primary rat hepatocytes should more accurately reflect the state of an authentic infected cell, clarify the disparate HBx activites that have been reported, and provide a more sophisticated understanding of the role of HBx during HBV replication.